Loss of USP28 and SPINT2 expression promotes cancer cell survival after whole genome doubling

Cell Oncol (Dordr). 2022 Feb;45(1):103-119. doi: 10.1007/s13402-021-00654-5. Epub 2021 Dec 28.

Abstract

Background: Whole genome doubling is a frequent event during cancer evolution and shapes the cancer genome due to the occurrence of chromosomal instability. Yet, erroneously arising human tetraploid cells usually do not proliferate due to p53 activation that leads to CDKN1A expression, cell cycle arrest, senescence and/or apoptosis.

Methods: To uncover the barriers that block the proliferation of tetraploids, we performed a RNAi mediated genome-wide screen in a human colorectal cancer cell line (HCT116).

Results: We identified 140 genes whose depletion improved the survival of tetraploid cells and characterized in depth two of them: SPINT2 and USP28. We found that SPINT2 is a general regulator of CDKN1A transcription via histone acetylation. Using mass spectrometry and immunoprecipitation, we found that USP28 interacts with NuMA1 and affects centrosome clustering. Tetraploid cells accumulate DNA damage and loss of USP28 reduces checkpoint activation, thus facilitating their proliferation.

Conclusions: Our results indicate three aspects that contribute to the survival of tetraploid cells: (i) increased mitogenic signaling and reduced expression of cell cycle inhibitors, (ii) the ability to establish functional bipolar spindles and (iii) reduced DNA damage signaling.

Keywords: Cancer; Cell cycle arrest; Multipolarity; NuMA1; SPINT2; Tetraploidy; USP28.

MeSH terms

  • Cell Cycle Checkpoints / genetics
  • Cell Survival / genetics
  • HCT116 Cells
  • Humans
  • Membrane Glycoproteins* / genetics
  • Neoplasms*
  • Tetraploidy
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin Thiolesterase* / genetics
  • Ubiquitin Thiolesterase* / metabolism

Substances

  • Membrane Glycoproteins
  • SPINT2 protein, human
  • Tumor Suppressor Protein p53
  • USP28 protein, human
  • Ubiquitin Thiolesterase